Tag: tacrolimus

Solid organ transplantation is a procedure that has saved untold millions of lives. Unfortunately, the tendency for an organ to be rejected by the immune system of the organ recipient is a formidable problem that is addressed in two ways. One of these is through tissue matching of the organ to the recipient. The other is through the use of immunosuppressive drugs that suppress the immune system. Neither one of these strategies is without caveats.

Tissue typing begins with a blood test to determine the organ recipient’s blood type. If the organ contains a blood type that is incompatible with the immune system of the organ recipient, the result will be catastrophic. Hyperacute rejection is the name given to organ rejection that occurs minutes to hours after the organ was transplanted. Hyperacute rejection occurs because the recipient has pre-existing antibodies in their body that recognizes and begins to destroy the graft. These antibodies can result from prior blood transfusions, multiple pregnancies, prior transplantation, or xenografts against which humans already have antibodies. Massive blood clotting within the capillaries of the organ clog the blood vessels and prevent perfusion of the graft with blood. The organ must come out or the patient will die.

Human cells have on their surfaces particular proteins that are encoded by genes located on the short arm of chromosome 6 called the major histocompatibility complex or MHC. the MHC genes encode human leukocyte antigens or HLAs. HLA proteins are extremely variable from person to person, and this seems to be the case because the more variation we have in our HLA proteins, the better job the immune system does recognizing foreign invaders.

Each individual expresses MHC genes from each chromosome. Therefore, your cells contain a mosaic of surface proteins, some of which are encoded by the HLAs encoded by the chromosome you inherited from your father and others of which are encoded by the chromosome your inherited from your mother.

The MHC molecules are divided into 2 classes. Class I molecules are normally expressed on all nucleated cells, but class II molecules are expressed only on the so-called “professional antigen-presenting cells” or APCs. APCs include cells that have names like dendritic cells, activated macrophages, and B cells. T lymphocytes only recognize foreign substances when they are bound to an MHC protein. Class I molecules present antigens from within the cell, which includes bits from viruses, tumors and things like that. Class II molecules present extracellular antigens such as extracellular bacteria and so on to a subclass of T cells called T helper cells, which express a molecule called “CD4” on their cell surface.

All this might seem very confusing, but it is vital to ensuring that the organ is properly received by the organ recipient. Some types of MHC are very different and will elicit robust immune responses against them, but others are not as different and can be rather well tolerated. How does the doctor which are which? Through three tests: 1) Blood type is the first one. If this does not match, you are out of luck; 2) lymphocytotoxicity assay in which blood from a patient is tested to determine if it reacts with lymphocytes from the blood of the donor. A positive crossmatch is a contraindication to transplantation because of the risk of hyperacute rejection. This is used mainly in kidney transplantation; 3) Panel-reactive antibody (PRA) screens in which the the serum of a patient is screened for antibodies against the lymphocytes from the donor. The presence of such antibodies is contraindicated for transplantation. Finally, there is a test that is not used a great called the mixed lymphocyte reaction test that uses lymphocytes from the blood of the organ donor and the organ recipient to see if they activate one another. This test takes a long time and can be difficult to interpret.

Once the patient receives the transplant, they are usually put on immunosuppressive drugs. These drugs include cyclosporine, tacrolimus, sirolimus, mycophenolate, and azathioprine. Each of these drugs has a boatload of side effects that range from hair loss, diabetes mellitus, nerve problems, increased risk of illness and tumors, and so on. None of these side effects are desirable, especially since the drug must be taken for the rest of your life after you receive the transplant.

Enter a new paper from University Hospital in Regensburg, Germany from the laboratory of Marc Dahkle that used particular stem cells from bone marrow to induce toleration of grafted heart tissue in laboratory animals without any drugs. This paper was published in Stem Cells Translational Medicine and is potentially landmark in what it shows.

In this paper, Dahkle and his colleagues used stem cells from the bone marrow known as multipotential adult progenitor cells or MAPCs. MAPCs have been thought to be a subtype of mesenchymal stem cell in the bone marrow because they have several cell surface markers in common. However, there are some subtle differences between these two types of cells. First of all, the MAPCs are larger than their mesenchymal stem cell counterparts. Secondly, MAPCs can be cultured more long-term, which increases the attractiveness of these cells for therapeutic purposes.

In this paper, the Dahkle group transplanted heart tissue from two unrelated strains of rats. Four days before the transplantation, the donor rats received an infusion of MAPCs into their tail veins. There were a whole slew of control rats that were used as well, but the upshot of all this is that the rats that received the MAPCs before the transplantation plus a very low dose of the immunosuppressive drug mycophenolate did not show any signs of rejection of the transplanted heart tissue. If that wasn’t enough, when the transplanted heart tissue was then extirpated and re-transplanted into another rat, those grafts that came from MAPC-treated rats survived without any drugs, but those that came from non-MAPC-treated rats did not.

Because control experiments showed that the rats treated with cyclosporine did not reject their grafts, Dahkle and others used this system to determine the mechanism by which MAPCs prevent immune rejection of the grafted tissue. They discovered that the MAPCs seem to work though a white blood cell called a macrophage. Somehow, the MAPCs signal to the macrophages to suppress rejection of the graft. If a drug (clodronate) that obliterates the macrophages was given to the rats with the MAPCs, the stem cells were unable to suppress the immunological rejection of the graft.

In this paper, the authors conclude that “When these data are taken together, our current approach advances the concept of cell-based immunomodulation in solid organ transplantation by demonstrating that third-party, adherent, adult stem cells from the bone marrow are capable of acting as a universal cell product that mediates long-term survival of fully allogeneic organ grafts.” Revolutionary is a good word for this findings of this paper. Hopefully, further pre-clinical trials will eventually give way to clinical trials in human patients that will allow human patients to have their lives saved by an organ transplant without the curse of taking immunosuppressive drugs for the rest of their lives.